Semi-synthetic and totally synthetic analogs of the natural fermentation products compactin and mevinolin have been found to be useful in limiting cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase. Most semi-and totally synthetic analogs have the following general structural formulae: ##STR1## wherein Z is ##STR2## wherein Q is ##STR3## Z.sub.2 is H or OH; Z.sub.1 is straight chain or branched C.sub.1-10 alkyl, or C.sub.1-10 alkyl substituted with hydroxyl, phenyl or substituted phenyl, cycloalkyl, C.sub.1-8 alkanoyloxy, alkylthio or phenylthio; a, b, c, and d represent optional double bonds, especially where b and d represent double bonds or a, b, c, and d are all single bonds; provided that when a is a double bond Q is ##STR4## or Z is ##STR5## where Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4 and Z.sup.5 independently are hydrogen,
halogen, PA2 C.sub.1-4 alkyl, PA2 C.sub.1-4 haloalkyl, PA2 hydroxy-C.sub.1-4 alkyl PA2 C.sub.1-8 alkanoyloxy C.sub.1-4 alkyl, or PA2 C.sub.7 or C.sub.11 aroyloxy-C.sub.1-4 alkyl PA2 (a) trialkylsilyloxy-C.sub.1-10 alkyl such as tert-butyldimethylsilyloxy-C.sub.1-10 alkyl or a like hydroxyl protecting group; PA2 (b) triphenylmethylthio-C.sub.1-10 alkyl; PA2 (c) C.sub.1-8 alkanoyloxy-C.sub.1-4 alkyl; PA2 (d) ##STR7## in which m is 0 to 3 and R.sub.7 is C.sub.1-5 alkyl; (e) ##STR8## in which R.sub.8 and R.sub.9 are independently C.sub.1-5 alkyl or R.sub.8 and R.sub.9 together with the nitrogen atom to which they are attached form a heterocycle selected from piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl or thiomorpholinyl; PA2 (f) ##STR9## in which q is 0 to 2 and R.sub.10 is C.sub.1-5 alkyl or phenyl; X and Y independently are hydrogen, halogen, trifluromethyl, C.sub.1-3 alkyl, C.sub.1-3 alkyloxy, C.sub.1-3 alkylthio, ##STR10## and ##STR11## and OR is (a) ##STR12## wherein R.sub.11 is hydrogen, or trialkylsilyloxy or alkyldiarylsilyloxy;
wherein one of Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4, Z.sup.5 contains an ester functionality. PA1 R.sub.1 and R.sub.2 are independently H or C.sub.1-10 alkyl or R.sub.1 and R.sub.2 together with the carbon atom to which they are attached form a carbocyclic ring of 3 to 8 carbon atoms; PA1 R.sub.3 and R.sub.4 are independently H or C.sub.1-3 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-3 alkylthio, phenyl, phenylthio or substituted phenyl in which the substituents are X and Y and when n is 2 to 5, each of the R.sub.3 s and R.sub.4 s are independently hydrogen, C.sub.1-3 alkyl, C.sub.3-7 cycloalkyl or only one of the R.sub.3 s and R.sub.4 s is phenyl or substituted phenyl; PA1 R.sub.5 is hydrogen, halogen, C.sub.1-10 alkyl, phenyl or substituted phenyl in which the substitutents are X and Y, or R.sub.5 is a group selected from: PA1 A is ##STR13## in which R.sub.13 is hydrogen or trialkylsilyloxy or alkyldiarylsilyloxy, a, b, c, d represent single bonds, one of a, b, c, or d represents a double bond or both a and c or both b and d represent double bonds, provided that when a is a double bond, A is ##STR14## or (b) ##STR15## wherein E is CH.sub.2 --CH.sub.2 or CH.dbd.CH; R.sub.15 R.sub.16 R.sub.17 R.sub.18 and Rhd 19 independently are PA1 (i) ##STR17## or a compound of structure (ii), (ii) ##STR18## wherein R'.sub.15 R'.sub.16 R'.sub.17 R'.sub.18 R'.sub.19 are defined as R.sub.15 R.sub.16 R.sub.17 R.sub.18 R.sub.19 respectively provided that when R.sub.15 R.sub.16 R.sub.17 R.sub.18 or R.sub.19 is oxy-C.sub.1-4 alkyl or oxy- then R'.sub.15 R'.sub.16 R'.sub.17 R'.sub.18 or R'.sub.19 is hydroxy-C.sub.1-4 alkyl or hydroxy- respectively;
In the polyhydronapthyl derivatives the C-8-ester functionality is typically inserted by acylation of the C-8-alcohol with the appropriate acyl chloride. This reaction generally requires prolonged high temperatures (100.degree. C., 18-36 hours) and large excesses of the often difficult to obtain acid chloride; however, even under these conditions the yields are low. In addition, the conditions of the acyl chloride reaction lead to a high percentage of undesired side product whereby a tertbutyldimethylsilyloxy radical, often present as a protecting group of alcohols, is eliminated from the .delta.-valerolactone moiety. Large amounts of starting alcohol and unconsumed acid chloride typically remain at the end of the reaction. These contaminants complicate isolation of product and result in lower yields of ester. The impurities also interfere with crystallization of subsequent intermediates. Similar problems may occur with acylation of alcohols in the biphenyl lactone derivatives, particularly where the alcohol involved is sterically hindered.
Acyl bromides are known in the literature (Chem Abstracts, 72, 42844 (1970) and S. D. Saraf, M. Zakai, Synthesis, 612 (1973)). The synthesis of acyl iodides from acyl chlorides and sodium iodide in acetonitrile has been described by Hoffman and Haase, Synthesis, 715, (1981).